DESCRIPTION (modified from the principal investigator's application): Involuntary movement disorders are a major cause of disability. The principal investigator proposes to study paroxysmal dystonic choreoathetosis (PDC), an inherited disorder characterized by attacks of involuntary movements that occur spontaneously at rest and often following caffeine or alcohol consumption. The cause of PDC is unknown and treatments are generally unsatisfactory. The overall goal of this investigation is to understand the cause and treatment of PDC. Understanding the molecular genetic cause of PDC will provide insight into PCD's pathophysiology and hopefully, into the cause and treatments of common movement disorders, including other paroxysmal dyskinesia, idiopathic dystonia, Tourette syndrome, Parkinson's disease, neuroleptic-induced tardive dyskinesia and extrapyramidal cerebral palsy. Moveover, understanding the molecular basis of PDC will suggest mechanisms by which alcohol and caffeine provoke PDC attacks. This insight will advance our understanding of the complex neurophysiologic effects of alcohol and caffeine. As Preliminary Data, he reports discovery of a genetic locus for PDC on chromosome 2q33-35. The PDC locus spans 6cM. The principal investigator and his group are collaborating with Dr Thomas Bird and Dr Wendy Raskind (University of Washington, Seattle) to analyze an unrelated PDC kindred that is also linked to this locus. Many important candidate genes are near the PDC locus including a cluster of ion channel genes. Four other paroxysmal neurologic disorders are due to mutations in ion channel genes. Since PDC is a paroxysmal, they propose that PDC is also due to an ion channel gene mutation. They propose to evaluate currently known genes on chromosome 2q33-35 and search for mutations in neurologically relevant genes that are physically mapped to the locus. As Preliminary Data, they report progress evaluating sodium hydrogen anion exchanger (AE3) gene; AE3 is completely linked with PDC. The principal investigator determined AE3's genomic organization and is now evaluating AE3 for mutations in PDC patients. Also as Preliminary Data, the principal investigator describes a nearly complete YAC contig that spans the PDC locus. He hopes to close the gaps in this contig. If he excludes known candidate genes, he will identify novel genes expressed from this contig. The proposed investigation will find the PDC gene and its mutations. Future proposals will study the physiologic consequences of this mutation. Understanding the molecular basis of PDC will help elucidate the causes of their inherited and acquired movement disorders including those listed above and provide insight into the physiology of alcohol and caffeine, which induce PDC attacks. This proposal deals exclusively with identification of the abnormal gene responsible for PDC. Previously criticized studies related to the PET scanning were removed from the present application. The Specific Aims, as related to the genetic analysis, of this application are the same as in original application, except the Aim 2, which is new and relates to the evaluation chromosome 2q33-35 Expressed Sequence Tagged Sites (ESTS). The Specific Aims, their rationale and methodology are described in a satisfactory fashion. The principal investigator has made progress since the time that first application has been submitted. He reduced the PDC gene locus from 6cM to 5cM. He excluded one candidate gene. He has made significant progress toward sequencing another candidate gene, anion exchanger (AE3) gene. AE3 gene is completely linked to the PDC locus in three of the four families and partially linked in the fourth family. AE3 gene is expressed in the brain, so its complete analysis in PDC should be important. In addition the principal investigator gained experience in isolating YACs from endogenous yeast chromosome DNA and isolated many YACs that constitute the nearly complete YAC contig spanning the PDC locus. There is no major criticism in relation to methodology and the design of the proposal. The concern relates to the fact that there are currently only four PDC available families, and it is uncertain whether more families will be identified. Therefore, only 3 years of funding is recommended in order to be able to evaluate progress.